Action of peptides derived from the natural protein EcTI combined with Temozolomide in glioblastoma cells

• Grant number: 21/13063-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2022
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Maria Luiza Vilela Oliva
• Grantee: Ana Beatriz da Silva Teixeira
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 17/06630-7 - Fragments derived from the structure of protease inhibitors with selectivity for inhibition of mammalian and microorganism enzymes and its role as an anti-inflammatory, antimicrobial, antithrombotic and anti- tumor agent: mechanism of action, AP.TEM

Abstract

The term glioblastoma refers to astrocytoma with the highest level of malignancy (grade IV), and even though its incidence is low when compared to other malignant tumors, it is one of the most lethal human tumors, with only a 12-15 months period of survival. These tumors can be classified according to the existence of a pre-lesion, such as secondary glioblastomas, which develop from lower-grade astrocytoma, while primary glioblastomas arise de novo. Due to the differences in genetic alterations identified in each case, primary and secondary glioblastomas are pathologies that develop through distinct genetic pathways and, consequently, protein expression profiles. These differences can affect sensitivity to treatment and should be taken into account in research for therapeutic alternatives. Standard treatment for glioblastoma remains palliative, instead of curative, including surgery, radiotherapy, and administration of the alkylating agent Temozolomide (TMZ). The Temozolomide induces cell death through DNA methylation, which causes cell cycle arrest-inducing double-strand breaks and, leads to apoptosis. The rare therapeutic options for glioblastoma allied to the development of resistance to TMZ and the debilitating side effects of the available chemotherapy are motivating factors to find alternative or auxiliary methods for this pathology. As the overexpression of proteases in the tumor microenvironment contributes to several aspects of cancer, inhibitors capable of decreasing the activity of these enzymes have great potential as a therapeutic alternative. The natural inhibitor I was actively antitumorigenic in glioblastoma cells, as published previously by our group. In this view, the aim of this project is to investigate the antitumor properties of synthetic peptides derived from the EcTI in glioblastoma cells, U87, and healthy astrocytes, investigating and comparing if its effect is similar to native protein and if it can potentiate the effect of the Temozolomide. The goal will be achieved through viability, proliferation, adhesion, migration, invasion, death, and cell cycle assays, in addition to evaluating a cell-peptide interaction, cytokines, and reactive oxygen species, involved in the tumor malignancy.(AU)